The Mentored Clinical Scientist Research Career Development Award (K08) from NIDCR will provide the applicant with training for a successful, academic career and scientific independence as a dentist-scientist. Enamel formation results in the hardest biomineral of the human body. Disturbances of enamel formation result in a hypoplastic or hypomineralized enamel layer or inherited or environmental origin. To develop into an expert in enamel pathophysiology, a training plan consisting of didactic courses and experimental techniques is proposed. The experimental plan aims to study the role of enamel matrix proteins for ameloblast cell differentiation and enamel formation though feedback mechanism. My previous work on the enamel matrix protein ameloblastin (Ambn) has identified the major cleavage site that generates fragments with opposing localizations and opposing fates. Ambn is essential to proper enamel formation, as enamel is absent in mice null for Ambn, but is regained in a dose-dependent manner when supplied as an Ambn transgene. These findings lead to the hypothesis that ameloblasts receive feedback signal from the enamel matrix to regulate their function and enamel mineralization. In Aim 1 the role of Ambn in ameloblasts differentiation is defined in vivo. In Aim 2 the relevance of Ambn cleavage is determined by mutating the major cleavage site. In Aim 3 potential feedback mechanisms via removal of enamel proteins are explored. The long-term goal is to understand the signaling pathways between enamel matrix and ameloblasts as an approach to new diagnostic and therapeutic strategies in dentistry. These studies directed at cellular mechanisms for enamel mineralization have impact on the daily dental practice. PUBLIC HEALTH RELEVANCE: Enamel is central to oral health, and its inherited or acquired pathologies have great impact on the quality of life and health in the general population. We propose studies to understand how enamel formation and ameloblasts are regulated by the enamel matrix, which will impact the diagnosis, and treatment of affected individuals.